rs28943591
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000414.4(HSD17B4):c.1471G>A(p.Ala491Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00495 in 1,585,784 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000414.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HSD17B4 | NM_000414.4 | c.1471G>A | p.Ala491Thr | missense_variant | Exon 17 of 24 | ENST00000510025.7 | NP_000405.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00354 AC: 539AN: 152060Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.00344 AC: 864AN: 251252Hom.: 3 AF XY: 0.00348 AC XY: 472AN XY: 135810
GnomAD4 exome AF: 0.00509 AC: 7303AN: 1433606Hom.: 23 Cov.: 25 AF XY: 0.00499 AC XY: 3566AN XY: 715194
GnomAD4 genome AF: 0.00355 AC: 540AN: 152178Hom.: 2 Cov.: 32 AF XY: 0.00294 AC XY: 219AN XY: 74390
ClinVar
Submissions by phenotype
not provided Benign:7
- -
- -
- -
- -
- -
- -
HSD17B4: BP4, BS2 -
not specified Benign:4
Ala516Thr in exon 18 of HSD17B4: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (48/8596) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs28943591). -
Variant summary: HSD17B4 c.1471G>A (p.Ala491Thr) results in a non-conservative amino acid change located in the MaoC-like dehydratase domain (IPR002539) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0034 in 251252 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in HSD17B4 causing D-Bifunctional Protein Deficiency phenotype (0.003), strongly suggesting that the variant is benign. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as benign (n=4) and likely benign (n=5). Based on the evidence outlined above, the variant was classified as benign. -
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
- -
Bifunctional peroxisomal enzyme deficiency Benign:2
- -
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome Benign:1
- -
Perrault syndrome 1 Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Bifunctional peroxisomal enzyme deficiency;C4551721:Perrault syndrome 1 Other:1
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at